Purified tissue plasminogen activator has only weak activity toward human plasminogen. However, in the presence of a fibrin clot or in the presence of a class of proteins which, for lack of a better name, we are calling "cofactors," the activity of tissue activator is enhanced over 100-fold, such that it then displays activity comparable to urokinase (approximately 200,000 International Units/mg). This control mechanism obviously will serve to localize generation of plasmin to areas where a clot or "cofactors" are located. The clot stimulatory effect has been widely observed; the stimulation by "cofactors" has not been reported by other groups. Our major present effort, besides purification and characterization of tissue activator, is characterization of this "cofactor" stimulatory mechanism. Our studies to date indicate (1) that no native proteins examined, fats or carbohydrates possess stimulatory ability, (2) denatured proteins are potent "cofactors," and (3) the "cofactor" effect of denatured proteins is dependent on lysine residues, as indicated by modification studies. Our working hypothesis is that tissue activator generates plasmin, which can digest most proteins, only in the presence of unhealthy protein, leading to its elimination from the body. This suggests a broader role for tissue activator in overall tissue remodeling, in addition to its previously suggested role in fibrinolysis.